Kindling, an animal model of termporal lobe spilepsy, is a phenomenon in which repeated administration of an initially subconvulsant electrical stimulus eventually results in intense limbic and motor seizures. Once established, the kindling effect is permanent. The mechanisms responsible for this phenomenon are unknown. Modulation of chemical synaptic transmission is likely an important determinant of this permanent state of abnormal neuronal excitability. Among the putative chemical transmitters studied to date, endogenous norepinephrine (NE) has been demonstrated to exert a powerful inhibitory effect on kindling development. The adrenergic receptor subtype with which NE interacts to inhibit kindling development is unknown. In preliminary studies we have found that systemic treatment with alpha2 adrenergic receptor antagonists markedly facilitates the rate of kindling development. We have also found that systemic treatment with an alpha2 receptor agonist markedly retards the rate of kindling development. The objective of this proposal is to employ pharmacological, electrophysiological, and radiohistochemical techniques to test three hypotheses related to these findings: (1) the inhibitory effects of endogenous NE are produced through interactions with alpha2 adrenergic receptors residing on targets of NE neurons; (2) part of the molecular basis of kindling is a reduction of alpha2 adrenergic receptors and/or recrptor coupled responses; and (3) the site of kindling stimulation is the site at which NE acts to inhibit kindling development. Insights derived from understanding the role of this transmitter may serve as a model for understanding the role of other transmitters in the kindling model. Such insights may lead to an understanding of the mechanisms underlying kindling itself. Finally, and perhaps most importantly, the kindling-inhibitory effects of the alpha2 agoinst, clonidine--a drug in current clinical use as an antihypertensive ageng--may lead to novel strategies for prophylaxis againts epilepsy arising as a late sequel to brain injury.